Alcohol abuse is a major public health problem in the United States and world-wide, and alcohol consumption by young individuals is rising. The direct effects of alcohol on the skeleton lead to reduced bone formation. In adults, alcohol- related osteopenia increases fracture incidence; fracture incidences rise in postmenopausal estrogen-deficient females who also use alcohol. There are no current therapeutic approaches to restore bone loss due to alcohol-induced damage. We will therefore test the hypothesis that bisphosphonate therapy during chronic alcohol ingestion reduces alcohol-induced damage to bone. Our preliminary results indicate that for one bisphosponate, alendronate (Fosamax) trabecular bone mineral density is increased during chronic alcohol ingestion in male rats. These preliminary data suggest that the bisphosphonates may be ideal therapeutic agents in restoring bone loss associated with alcohol-induced osteopenia. We will test our hypothesis for the bisphosphonates alendronate, clodronate, ibandronate and pamidronate at both a high and low dose. These in vivo studies will compare the effects of bisphosphonates in age- and gender-related experiments. In Specific Aim number 1 we will test these bisphosphonates in adolescent male and female rats during skeletal modeling during chronic alcohol intake. In Specific Aim number 2 we will test these bisphosphonates in adult male and female adult rats undergoing skeletal remodeling during chronic alcohol ingestion. In Specific Aim number 3 we will test these bisphosphonates in parallel with parathyroid hormone in sham-operated and ovariectomized adult female rats to determine their effectiveness in estrogen-depleted animals during chronic alcohol ingestion. We will compare the dose-related therapeutic interventions by measuring serum hormonal changes for IGF-1, testosterone, luteinizing hormone (ICSH), estradiol, and osteocalcin, for trabecular and cortical bone mineral density by quantitative computerized tomography, for metaphyseal bone gene expression of type I collagen, osteocalcin, and bone-specific alkaline phosphatase, for cortical bone biomechanical properties, and for trabecular and cortical bone histomorphometric parameters. We expect that the various types and doses of the bisphosphonates (chosen on the basis of their antiresorptive potencies) will differ in their effects on these skeletal tissues during chronic alcohol ingestion.